Obesity and obesity-related cardiovascular complications are an increasing health burden in the United States. An analysis of nearly 2 million veterans receiving care at VA Medical Centers in 2000 indicated that ~68% were overweight and ~37% were obese. The medical costs associated with obesity strain the VA health care system. Obesity is an established risk factor for cardiovascular disease (CVD) and stroke, and the cardiovascular complications of obesity are a leading cause of potentially preventable death in Veterans. In addition to contributing to traditional CVD risk factors, obesity is also characterized by a chronic sub-acute inflammatory state with macrophage infiltration in fat and the production of inflammatory mediators by adipose tissue. Inflamed adipose tissue may uniquely contribute to systemic inflammatory mediators that promote the development of atherosclerosis. A better understanding of the role of adipose tissue in generating inflammatory mediators will ultimately result in identification of novel strategies to prevent and treat associated CVD. Recent evidence and our own findings indicate that adipose tissue contributes to systemic levels of the secreted lysophospholipase D autotaxin (ATX). ATX is responsible for production of extracellular, biologically active lysophosphatidic acid (LPA), a bioactive lipid present in physiologically relevant levels in plasma and other biologic fluids that is positioned to play a role in human health and disease. Based on observations that ATX expression increases with adiposity and demonstrated effects of ATX and LPA on monocyte migration and endothelial permeability, we propose the central hypothesis that signaling pathways regulated by ATX contribute to obesity associated inflammation and the development of atherosclerosis. We will test our central hypothesis using state-of-the art genetic and pharmacologic approaches in two specific aims. In Aim One, we will identify the role of adipose derived ATX in local and systemic inflammation. In Aim Two, we will identify the role of adipose-derived ATX in the development of atherosclerosis. The aims of this grant provide a vehicle to address a major unresolved issue in the field of lysolipid signaling, namely role of adipose-derived ATX in biologic signaling mediated by LPA and its role in atherosclerosis These results will be significant, because they are expected to provide innovative targets and provide proof-of-concept for novel inhibitors that may be used for prevention and treatment of the cardiovascular complications of obesity in humans.